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Systematic identification of anticancer drug targets reveals a nucleus-to-mitochondria ROS-sensing pathway

2023; Cell Press; Volume: 186; Issue: 11 Linguagem: Inglês

10.1016/j.cell.2023.04.026

1097-4172

Junbing Zhang, Claire Simpson, Jacqueline Berner, Harrison B. Chong, Jiafeng Fang, Zehra Ordulu, Tommy Weiss‐Sadan, Anthony Possemato, Stefan Harry, Mariko Takahashi, Tzu-yi Yang, Marianne Richter, Himani Patel, Abby E. Smith, Alexander Carlin, Adriaan F. Hubertus de Groot, Konstantin Wolf, Lei Shi, Ting-Yu Wei, Benedikt R. Dürr, Nicholas J. Chen, Tristan Vornbäumen, Nina Olivera Wichmann, Mohammed Mahamdeh, Venkatesh Pooladanda, Yusuke Matoba, Shaan Kumar, Eugene Kim, Sara Bouberhan, Esther Oliva, Bo R. Rueda, Roy J. Soberman, Nabeel Bardeesy, Brian B. Liau, Michael S. Lawrence, Matt P. Stokes, Sean A. Beausoleil, Liron Bar‐Peled,

Redox biology and oxidative stress

Summary Multiple anticancer drugs have been proposed to cause cell death, in part, by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs, exactly how the resultant ROS function and are sensed is poorly understood. It remains unclear which proteins the ROS modify and their roles in drug sensitivity/resistance. To answer these questions, we examined 11 anticancer drugs with an integrated proteogenomic approach identifying not only many unique targets but also shared ones—including ribosomal components, suggesting common mechanisms by which drugs regulate translation. We focus on CHK1 that we find is a nuclear H 2 O 2 sensor that launches a cellular program to dampen ROS. CHK1 phosphorylates the mitochondrial DNA-binding protein SSBP1 to prevent its mitochondrial localization, which in turn decreases nuclear H 2 O 2 . Our results reveal a druggable nucleus-to-mitochondria ROS-sensing pathway—required to resolve nuclear H 2 O 2 accumulation and mediate resistance to platinum-based agents in ovarian cancers.